Leukemia survivors and others who received bone marrow transplants have a markedly increased risk of developing solid tumors later in life, according to a study sponsored by the National Cancer Institute (NCI) and published in the March 27 New England Journal of Medicine.*

The increased risk of a new cancer was related to a combination of factors including the radiation received in preparation for the transplant, altered immune function, and prior treatment for the initial disease, said Rochelle Curtis, who led the study at NCI's Radiation Epidemiology Branch.

This is the largest study to date to show that patients who received an allogeneic transplant -- using marrow from a "matched" healthy donor -- have an increased risk of developing solid tumors, such as melanoma and brain and thyroid cancers, after transplantation. The study did not address autologous transplantation, which uses the patient's own marrow or stem cells and is now under study in the treatment of breast and ovarian cancer.

The findings underline the importance of lifelong checkups for cancer survivors who have had bone marrow transplants. "Our results should alert physicians and patients to the higher risk of new solid cancers after transplantation," Curtis said. "Transplant recipients should be followed indefinitely to detect early signs of cancer."

To determine the risk of solid tumors, the researchers analyzed a database of about 19,000 patients from the International Bone Marrow Transplant Registry, Milwaukee, and the
Fred Hutchinson Cancer Research Center in Seattle. Data were contributed by 235 transplant centers in more than 40 countries. Most of the patients in the study had received a transplant to treat leukemia or severe aplastic anemia, using marrow from matched siblings.

A total of 80 patients developed solid tumors, 2.7 times more than would be expected in the general population. The risk rose steeply with time since transplantation. Five to nine years after transplantation, the incidence of solid tumors was 4.1 times higher among transplant recipients than in the general population, and after 10 years, the risk was 8.3 times higher among transplant recipients.

Transplant patients had significantly higher rates of melanoma and tumors in the buccal cavity (lip, mouth, tongue, and salivary glands). The increase in risk was also significant for cancers of the liver, brain and other parts of the central nervous system, thyroid, bone, and connective tissue.

The risk rose with increasing dose of radiation received in conjunction with the transplant and was highest among those who had the highest doses. Ionizing radiation has been linked in other studies to thyroid, bone, connective tissue, and brain cancers.

Age at the time of transplantation also affected risk. Patients younger at the time of transplant -- under age 30 -- were more likely to develop a solid tumor later in life. The highest risks were among those who had undergone transplantation when they were less than 10 years old. Many of these excess cancers were related to prior radiation therapy.

Immunologic factors appeared to affect risk for certain cancers, such as melanoma and cancers of the oral cavity and skin. Patients, particularly men, who had developed chronic
graft-versus-host disease after transplantation -- a disorder in which immune cells from the transplanted marrow attack the patient's skin and internal organs -- were more likely to develop squamous cell cancers of the skin, mouth, tongue, and lips.

Most of the data in this study came from patients followed less than 10 years. Among the 19,000 patients, only 690 were followed for ten or more years and only 104 were followed for 15 years or more. The authors note that further research will be needed to clarify the long-term risk of solid cancers after bone marrow transplantation, especially for breast, lung, and other cancers that commonly take many years to develop.

The authors of this study emphasize that bone marrow transplantation cures many patients with cancer or other life-threatening diseases and produces long-term survival in a large number of other cases. "These benefits clearly outweigh the risks of late complications," said Curtis. "But among patients who have received transplants, constant vigilance is called for to detect signs of solid tumors early, when they are more treatable."

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